What is the mechanism of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2I) benefit in Heart Failure with preserved Ejection Fraction (HFpEF)?

From the Guidelines

SGLT2 inhibitors benefit patients with heart failure with preserved ejection fraction (HFpEF) through multiple mechanisms, primarily by promoting osmotic diuresis and natriuresis, improving cardiac energetics, reducing inflammation and oxidative stress, and preserving renal function, as demonstrated in the EMPEROR-Preserved trial 1. The primary mechanisms of SGLT2 inhibitors in HFpEF include:

• Promoting osmotic diuresis and natriuresis, which reduces preload and cardiac wall stress without activating the sympathetic nervous system
• Improving cardiac energetics by shifting metabolism from glucose to ketones and fatty acids, providing more efficient fuel sources for the failing heart
• Reducing inflammation and oxidative stress in cardiac tissue
• Decreasing myocardial fibrosis and improving arterial compliance
• Preserving renal function, which is crucial as cardiorenal syndrome often accompanies HFpEF These mechanisms collectively contribute to the significant reductions in heart failure hospitalizations and cardiovascular mortality observed in clinical trials of SGLT2 inhibitors in HFpEF patients, as seen in the EMPEROR-Preserved trial 1 and further supported by the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1 and the 2024 standards of care in diabetes 1. The standard dosing for these benefits includes empagliflozin 10mg daily or dapagliflozin 10mg daily, with effects typically seen within weeks to months of initiation, as demonstrated in the DELIVER trial 1. Key benefits of SGLT2 inhibitors in HFpEF include:
• Reduction in heart failure hospitalizations
• Reduction in cardiovascular mortality
• Improvement in quality of life
• Preservation of renal function
• Reduction in myocardial fibrosis and improvement in arterial compliance Overall, the use of SGLT2 inhibitors, such as empagliflozin or dapagliflozin, is recommended in patients with HFpEF to reduce the risk of worsening heart failure and cardiovascular death, as supported by the highest quality evidence from recent clinical trials 1.

From the FDA Drug Label

12 CLINICAL PHARMACOLOGY

1. 1 Mechanism of Action SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT G), and thereby increases urinary glucose excretion (UGE) Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure.

The mechanism of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2I) benefit in Heart Failure with preserved Ejection Fraction (HFpEF) is not directly stated in the provided drug label.

• The label describes the mechanism of action of canagliflozin, an SGLT2 inhibitor, in terms of its effects on glucose reabsorption and excretion.
• It also mentions the increase in delivery of sodium to the distal tubule and the potential reduction in intraglomerular pressure.
• However, it does not explicitly address the benefit of SGLT2I in HFpEF. Therefore, based on the provided information, no conclusion can be drawn about the mechanism of SGLT2I benefit in HFpEF 2.

From the Research

Mechanism of SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction (HFpEF)

The mechanism of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2I) benefit in Heart Failure with preserved Ejection Fraction (HFpEF) is not fully understood, but several biological mechanisms are thought to contribute to their beneficial effects. These include:

• Anti-inflammatory effects
• Reduction of fibrosis and apoptosis
• Improvement of myocardial metabolism
• Mitochondrial function optimization
• Oxidative stress protection
• Improvement of ventricular loading conditions by forcing diuresis and natriuresis
• Enhancement of vascular and renal function
• Reduction of myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins 3

Clinical Evidence

Several clinical trials have demonstrated the benefit of SGLT2 inhibitors in patients with HFpEF, including the EMPEROR-Preserved and DELIVER trials 4, 3. These trials have shown that SGLT2 inhibitors can reduce the risk of cardiovascular death and hospitalizations for heart failure in patients with HFpEF. The exact mechanisms by which SGLT2 inhibitors provide benefits for patients with HFpEF are likely to be multifactorial and may involve a combination of the biological mechanisms mentioned above.

Key Findings

Key findings from the clinical trials include:

• SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalization for heart failure in patients with HFpEF 4
• SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalizations for heart failure in a broad range of patients with heart failure, including those with HFpEF 4
• The treatment effects of SGLT2 inhibitors on cardiovascular outcomes were consistent across different patient subgroups, including those with HFpEF 4

Ongoing Research

Ongoing studies are being conducted to further evaluate the clinical benefit of SGLT2 inhibitors in patients with HFpEF 5. The results of these studies will provide additional insight into the mechanisms by which SGLT2 inhibitors benefit patients with HFpEF and will help to inform clinical practice.